Histone deacetylase inhibitors: multifunctional anticancer agents.

Acetylation and deacetylation of chromatin histone protein by histone deacetylase (HDAC) alters chromatin structure and dynamically affects transcriptional regulation. Many lines of evidence indicate that histone hypo-acetylation induces repression of tumour suppressor gene expression. Small molecule inhibitors of HDAC (HDACI) are highly effective in up-regulating tumour suppressor gene expression, reducing tumour growth and inducing programmed cell death in vitro and in cancer patients in phase I and II clinical trials. HDACI-induced growth inhibition and cytotoxicity have been attributed to acetylation of both histone and non-histone proteins. Less studied, but equally important, is the role of HDAC and HDACI on other components of the malignant phenotype: tumour initiation and progression. In this review, we summarise evidence indicating that the in vivo anti-cancer efficacy of HDACIs is at least in part dependent on suppression of cancer cell migration, invasion, metastasis, blood supply, and angiogenesis. As histone hypo-acetylation is involved in the tumourigenesis of various haematological and solid malignancies, the clinical use of HDACIs in patients at high risk of cancer or with precancerous conditions warrants further investigation.

[1]  L. Altucci,et al.  Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells , 2005, Nature Medicine.

[2]  Ricky W. Johnstone,et al.  Histone-deacetylase inhibitors: novel drugs for the treatment of cancer , 2002, Nature Reviews Drug Discovery.

[3]  R. W. Miller,et al.  Tumors in Rubinstein-Taybi syndrome. , 1995, American journal of medical genetics.

[4]  P. Wesseling,et al.  Vascular endothelial growth factor-A(165) induces progression of melanoma brain metastases without induction of sprouting angiogenesis. , 2002, Cancer research.

[5]  G. Bae,et al.  Apicidin, a Histone Deacetylase Inhibitor, Induces Apoptosis and Fas/Fas Ligand Expression in Human Acute Promyelocytic Leukemia Cells* , 2002, The Journal of Biological Chemistry.

[6]  Jorge A. Almenara,et al.  The histone deacetylase inhibitor MS-275 promotes differentiation or apoptosis in human leukemia cells through a process regulated by generation of reactive oxygen species and induction of p21CIP1/WAF1 1. , 2003, Cancer research.

[7]  Yang Shi,et al.  Ineffectiveness of Histone Deacetylase Inhibitors to Induce Apoptosis Involves the Transcriptional Activation of NF-κB through the Akt Pathway* , 2003, Journal of Biological Chemistry.

[8]  Y. Miller,et al.  γ-Catenin expression is reduced or absent in a subset of human lung cancers and re-expression inhibits transformed cell growth , 2002, Oncogene.

[9]  K. Somasundaram,et al.  Expression profiling of sodium butyrate (NaB)-treated cells: identification of regulation of genes related to cytokine signaling and cancer metastasis by NaB , 2004, Oncogene.

[10]  Sharon Roth,et al.  The Growth Suppressor PML Represses Transcription by Functionally and Physically Interacting with Histone Deacetylases , 2001, Molecular and Cellular Biology.

[11]  M. Goh,et al.  Phenylbutyrate inhibits the invasive properties of prostate and breast cancer cell lines in the sea urchin embryo basement membrane invasion assay , 2002, International journal of cancer.

[12]  F. Behm,et al.  All patients with the T(11;16)(q23;p13.3) that involves MLL and CBP have treatment-related hematologic disorders. , 1997, Blood.

[13]  Hee June Choi,et al.  Transcriptional regulation of a metastasis suppressor gene by Tip60 and β-catenin complexes , 2005, Nature.

[14]  Keith B Glaser,et al.  Trifluoromethyl ketones as inhibitors of histone deacetylase. , 2002, Bioorganic & medicinal chemistry letters.

[15]  S. Dhanasekaran,et al.  The polycomb group protein EZH2 is involved in progression of prostate cancer , 2002, Nature.

[16]  M. Michaelis,et al.  Valproic acid and interferon-α synergistically inhibit neuroblastoma cell growth in vitro and in vivo , 2004 .

[17]  H. Scher,et al.  The histone deacetylase inhibitor SAHA arrests cancer cell growth, up-regulates thioredoxin-binding protein-2, and down-regulates thioredoxin , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[18]  M. Carducci,et al.  Combination of phenylbutyrate and 13-cis retinoic acid inhibits prostate tumor growth and angiogenesis. , 2001, Cancer research.

[19]  P. Atadja,et al.  Histone deacetylase inhibitor LAQ824 both lowers expression and promotes proteasomal degradation of Bcr-Abl and induces apoptosis of imatinib mesylate-sensitive or -refractory chronic myelogenous leukemia-blast crisis cells. , 2003, Cancer research.

[20]  H. Kato,et al.  Histone Deacetylase 7 Associates with Hypoxia-inducible Factor 1α and Increases Transcriptional Activity* , 2004, Journal of Biological Chemistry.

[21]  Kristian Helin,et al.  EZH2 is downstream of the pRB‐E2F pathway, essential for proliferation and amplified in cancer , 2003, The EMBO journal.

[22]  T. Mima,et al.  Histone deacetylase inhibitors such as sodium butyrate and trichostatin A inhibit vascular endothelial growth factor (VEGF) secretion from human glioblastoma cells , 2006, Brain Tumor Pathology.

[23]  T. Yamano,et al.  Epigenetic up-regulation of C-C chemokine receptor 7 and C-X-C chemokine receptor 4 expression in melanoma cells. , 2005, Cancer research.

[24]  Debashis Ghosh,et al.  EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[25]  L. Neckers,et al.  Modulation of p53, ErbB1, ErbB2, and Raf-1 expression in lung cancer cells by depsipeptide FR901228. , 2002, Journal of the National Cancer Institute.

[26]  H. Kwon,et al.  Histone deacetylase inhibitor FK228 inhibits tumor angiogenesis , 2002, International journal of cancer.

[27]  Hidde Ploegh,et al.  Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis. , 2004, Molecular cell.

[28]  M. E. Robinson,et al.  Favorable Neuroblastoma Genes and Molecular Therapeutics of Neuroblastoma , 2004, Clinical Cancer Research.

[29]  Takeshi Inoue,et al.  Antitumor efficacy of FK228, a novel histone deacetylase inhibitor, depends on the effect on expression of angiogenesis factors. , 2003, Biochemical pharmacology.

[30]  Suk Woo Nam,et al.  Increased expression of histone deacetylase 2 is found in human gastric cancer , 2005, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[31]  R. Johnstone,et al.  Histone-Deacetylase Inhibitors for the Treatment of Cancer , 2004, Cell cycle.

[32]  Xin Bian,et al.  Ku70 acetylation mediates neuroblastoma cell death induced by histone deacetylase inhibitors. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[33]  Ping Zhu,et al.  Induction of HDAC2 expression upon loss of APC in colorectal tumorigenesis. , 2004, Cancer cell.

[34]  P. Munster,et al.  Valproic acid alters chromatin structure by regulation of chromatin modulation proteins. , 2005, Cancer research.

[35]  T. Tsuruo,et al.  A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo antitumor activity against human tumors. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[36]  R. Blaheta,et al.  Induction of differentiation and suppression of malignant phenotype of human neuroblastoma BE(2)-C cells by valproic acid: enhancement by combination with interferon-alpha. , 2002, International journal of oncology.

[37]  K. Matsusue,et al.  Characterization of mouse metastasis-associated gene 2: genomic structure, nuclear localization signal, and alternative potentials as transcriptional activator and repressor. , 2001, DNA and cell biology.

[38]  G. Perez,et al.  Role of thioredoxin in the response of normal and transformed cells to histone deacetylase inhibitors. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[39]  S. Scherer,et al.  Post-transcriptional Regulation of Endothelial Nitric-oxide Synthase by an Overlapping Antisense mRNA Transcript* , 2004, Journal of Biological Chemistry.

[40]  P. Marks,et al.  Hybrid polar histone deacetylase inhibitor induces apoptosis and CD95/CD95 ligand expression in human neuroblastoma. , 1999, Cancer research.

[41]  Eun-Joung Moon,et al.  Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes , 2001, Nature Medicine.

[42]  Gordon K Smyth,et al.  Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[43]  K. Rieger-Christ,et al.  Restoration of plakoglobin expression in bladder carcinoma cell lines suppresses cell migration and tumorigenic potential , 2005, British Journal of Cancer.

[44]  C. Van Lint,et al.  The expression of a small fraction of cellular genes is changed in response to histone hyperacetylation. , 1996, Gene expression.

[45]  Ricky W Johnstone,et al.  Histone deacetylase inhibitors in cancer therapy: is transcription the primary target? , 2003, Cancer cell.

[46]  P. Marks,et al.  Apoptotic and autophagic cell death induced by histone deacetylase inhibitors , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[47]  Lu Zhang,et al.  The Histone Deacetylase Inhibitor NVP-LAQ824 Inhibits Angiogenesis and Has a Greater Antitumor Effect in Combination with the Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor PTK787/ZK222584 , 2004, Cancer Research.

[48]  David B. Alexander,et al.  The Membrane-Anchored MMP Inhibitor RECK Is a Key Regulator of Extracellular Matrix Integrity and Angiogenesis , 2001, Cell.

[49]  G. Semenza,et al.  FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. , 2001 .

[50]  Marie Joseph,et al.  Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[51]  V. Castronovo,et al.  Expression of histone deacetylase 8, a class I histone deacetylase, is restricted to cells showing smooth muscle differentiation in normal human tissues. , 2004, The American journal of pathology.

[52]  C. Disteche,et al.  The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB–binding protein , 1996, Nature Genetics.

[53]  P. Atadja,et al.  Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B. , 2003, Molecular cancer therapeutics.

[54]  W. Hung,et al.  Histone deacetylase inhibitor up-regulates RECK to inhibit MMP-2 activation and cancer cell invasion. , 2003, Cancer research.

[55]  M. Yoshida,et al.  FR901228, a potent antitumor antibiotic, is a novel histone deacetylase inhibitor. , 1998, Experimental cell research.

[56]  L. Devy,et al.  Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling , 2002, Oncogene.

[57]  Lucia Altucci,et al.  Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway , 2005, Nature Medicine.

[58]  C. Allis,et al.  Taking LSD1 to a New High , 2005, Cell.

[59]  Sandip K. Mishra,et al.  Transcriptional repression of oestrogen receptor by metastasis-associated protein 1 corepressor , 2000, Nature Cell Biology.

[60]  S. Loitsch,et al.  Modulation of angiogenesis-related protein synthesis by valproic acid. , 2004, Biochemical and biophysical research communications.

[61]  D. Tilley,et al.  Vascular Smooth Muscle Cell Phenotype-Dependent Phosphodiesterase 4D Short Form Expression: Role of Differential Histone Acetylation on cAMP-Regulated Function , 2005, Molecular Pharmacology.

[62]  U. Förstermann,et al.  Inhibitors of Histone Deacetylation Downregulate the Expression of Endothelial Nitric Oxide Synthase and Compromise Endothelial Cell Function in Vasorelaxation and Angiogenesis , 2002, Circulation research.

[63]  R. Evans,et al.  Acquisition of oncogenic potential by RAR chimeras in acute promyelocytic leukemia through formation of homodimers. , 2000, Molecular cell.

[64]  G. Nicolson,et al.  Expression of the metastasis‐associated MTA1 protein and its relationship to deacetylation of the histone H4 in esophageal squamous cell carcinomas , 2004, International journal of cancer.

[65]  G. Hampton,et al.  Histone deacetylase 1 represses the small GTPase RhoB expression in human nonsmall lung carcinoma cell line , 2003, Oncogene.

[66]  V. Reinke,et al.  Regulation of tissue-specific and extracellular matrix-related genes by a class I histone deacetylase. , 2005, Molecular cell.

[67]  Rudolf Fahlbusch,et al.  Suberoylanilide hydroxamic acid (SAHA) has potent anti‐glioma properties in vitro, ex vivo and in vivo , 2005, Journal of neurochemistry.

[68]  D. Canes,et al.  Histone deacetylase inhibitors upregulate plakoglobin expression in bladder carcinoma cells and display antineoplastic activity in vitro and in vivo , 2005, International journal of cancer.

[69]  S. Inoue,et al.  Role of the histone deacetylase complex in acute promyelocytic leukaemia , 1998, Nature.

[70]  R. Evans,et al.  The LAZ3(BCL-6) oncoprotein recruits a SMRT/mSIN3A/histone deacetylase containing complex to mediate transcriptional repression. , 1998, Nucleic acids research.

[71]  Y. Mitani,et al.  Histone Acetylation and Gastrointestinal Carcinogenesis , 2003, Annals of the New York Academy of Sciences.

[72]  James R. Downing,et al.  ETO, a Target of t(8;21) in Acute Leukemia, Makes Distinct Contacts with Multiple Histone Deacetylases and Binds mSin3A through Its Oligomerization Domain , 2001, Molecular and Cellular Biology.

[73]  M. Fraga,et al.  Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer , 2005, Nature Genetics.

[74]  K. Glaser,et al.  Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines. , 2003, Molecular cancer therapeutics.

[75]  Yin-Won Lee,et al.  Apicidin is a histone deacetylase inhibitor with anti-invasive and anti-angiogenic potentials. , 2004, Biochemical and biophysical research communications.

[76]  J. Fish,et al.  The Expression of Endothelial Nitric-oxide Synthase Is Controlled by a Cell-specific Histone Code* , 2005, Journal of Biological Chemistry.

[77]  Hisham S. Elbatarny,et al.  Cyclic nucleotide phosphodiesterase activity, expression, and targeting in cells of the cardiovascular system. , 2003, Molecular pharmacology.

[78]  P. Jackson,et al.  KAI1 tetraspanin and metastasis suppressor. , 2005, The international journal of biochemistry & cell biology.

[79]  J. Barrett,et al.  KAI1, a metastasis suppressor gene for prostate cancer on human chromosome 11p11.2. , 1995, Science.

[80]  T. Iwama,et al.  p300 gene alterations in colorectal and gastric carcinomas. , 1996, Oncogene.

[81]  D. Coradini,et al.  Inhibition of Hepatocellular Carcinomas in vitro and Hepatic Metastases in vivo in Mice by the Histone Deacetylase Inhibitor HA-But , 2004, Clinical Cancer Research.

[82]  J. Winnie,et al.  Invasion of v-FosFBR-transformed cells is dependent upon histone deacetylase activity and suppression of histone deacetylase regulated genes , 2004, Oncogene.

[83]  A. Heerschap,et al.  Differential effects of vascular endothelial growth factor A isoforms in a mouse brain metastasis model of human melanoma. , 2003, Cancer research.

[84]  D. Frings,et al.  Butyrate impairs intestinal tumor cell-induced angiogenesis by inhibiting HIF-1α nuclear translocation , 2003 .

[85]  F. Lan,et al.  Regulation of LSD1 histone demethylase activity by its associated factors. , 2005, Molecular cell.

[86]  Chi-Wai Wong,et al.  Histone deacetylase associated with mSin3A mediates repression by the acute promyelocytic leukemia-associated PLZF protein , 1998, Oncogene.

[87]  P. Marks,et al.  Histone deacetylase inhibitors: development as cancer therapy. , 2004, Novartis Foundation symposium.

[88]  Rakesh Kumar,et al.  Emerging roles of MTA family members in human cancers. , 2003, Seminars in oncology.